DESCRIPTION (as provided by applicant): The myocardium possesses an inherent capacity for cellular replacement, yet this reparative process is inadequate to cope with acute injury or chronic stress. Remarkable advances are evident in the use of donated stem cell populations or expression of paracrine factors (or both) to enhance myocardial repair, but efficacy of adoptively transferred cells to generate new myocardium remains modest. Moreover, several studies indicate that repair stems predominantly from recruitment of endogenous cells activated by cellular or molecular therapeutic interventions. The overarching premise of this program is that endogenous myocardial reparative mechanisms become compromised by pathologic stimuli leading to a downward spiral of cardiac insufficiency linked to inadequate cellular replacement. Therefore, functional restoration of myocardial repair will inevitably require deciphering the molecular signaling that impairs cellular replacement and healing. Project 1 (Sussman) examines the role of extracellular matrix. Project 2 (Heller Brown) focuses upon G-protein coupled receptor signaling. Project 3 (Glembotski) is concerned with secretion / cardiokine synthesis, and Project 4 (Gustafsson) delineases the role of mitochondrial function in the regenerative process. Relieving pathologic impediments to cellular replacement will increase formation of functional myocardium and improve hemodynamic performance. Concurrent enhancement therapies to potentiate healing can then benefit from improved endogenous functional repair, leading to more effective compensation of the heart to pathologic stress. Pathological signals that impair survival, proliferation, migration, commitment, or integration of endogenous replacement cells into the stressed myocardium need to be defined, mitigated, and optimally reversed in order to restore myocardial repair. Projects in this program will demonstrate molecular mechanisms responsible for loss of reparative capacity that create nonpermissive conditions for expansion or retention of cardiogenic cells. The goal of this program will be to delineate these deleterious signaling mechanisms and determine how they can be overcome to restore endogenous cellular repair processes that heal the damaged heart.